Soluble MIC polypeptides as markers for diagnosis, prognosis and treatment of cancer and autoimmune diseases or conditions

Abstract

The present invention provides prognostic and diagnostic methods for cancer, as well as methods for monitoring or staging cancer. Methods involve assaying for tumor-derived soluble MIC polypeptide—either MICA or MICB or both—in a sample from a subject. Assays can be implemented with a MIC polypeptide binding agent such as a MIC polypeptide antibody or recombinant NKG2D. An ELISA sandwich assay is employed in some embodiments of the invention to identify a soluble MIC polypeptide. In additional embodiments, a sample is assayed for tumor cell-surface bound MIC in addition to assaying for soluble MIC. The invention also provides methods of cancer therapy involving detecting cancer in the subject by assaying for soluble MIC polypeptide and then administering a cancer therapy.

1. A method for modulating expression of NKG2D in a lymphocyte capable of expressing NKG2D comprising binding a tumor cell produced MIC polypeptide with a MIC polypeptide binding monoclonal antibody, wherein MIC suppressed NKG2D expression of the lymphocyte is increased. 
     
     
       2. The method of  claim 1 , wherein the antibody recognizes the α3 domain of MIC. 
     
     
       3. The method of  claim 1 , wherein the antibody is 6G6. 
     
     
       4. The method of  claim 1 , wherein the antibody recognizes the distal α1α2 domain of MIC. 
     
     
       5. The method of  claim 4 , wherein the antibody is 2C10, 6D4 or 3H5. 
     
     
       6. The method of  claim 1 , wherein the MIC polypeptide binding antibody binds soluble MIC. 
     
     
       7. The method of  claim 1 , wherein the MIC polypeptide binding antibody binds bound MIC. 
     
     
       8. The method of  claim 1 , wherein the cell is a T cell or natural killer cell. 
     
     
       9. A method comprising administering to a NKG2D expressing lymphocyte a neutralizing monoclonal antibody against tumor shed MIC, wherein MIC associated downmodulation of NKG2D in a the NKG2D expressing lymphocyte cell is inhibited. 
     
     
       10. A method for blocking downregulation of NKG2D on a lymphocyte comprising administering a MIC polypeptide binding monoclonal antibody that interacts with soluble MIC shed from a tumor cell, wherein the MIC polypeptide binding monoclonal antibody prevents shed MIC from binding NKG2D. 
     
     
       11. The method of  claim 9 , wherein the neutralizing antibody recognizes the α3 domain of MIC. 
     
     
       12. The method of  claim 9 , wherein the neutralizing antibody recognizes the distal α1α2 domain of MIC. 
     
     
       13. The method of  claim 9 , wherein the NKG2D expressing lymphocyte is a T cell. 
     
     
       14. The method of  claim 10 , wherein the NKG2D expressing lymphocyte is a T cell.